Obsessive-compulsive disorder (OCD) is a disabling illness that usually begins by adolescence. Our long- term goal is to identify effective new treatment approaches for OCD that target underlying brain mechanisms and help prevent the overwhelming morbidity caused by this illness. In this collaborative R34, we propose to evaluate the feasibility, efficacy, and potential causal mechanism of a novel treatment strategy for pediatric OCD: the addition of minocycline to serotonin reuptake inhibitors (SRI). Our rationale is threefold. First, the only proven SRI augmentation strategy in children and adolescents i the addition of cognitive-behavioral therapy (CBT)~ the addition of antipsychotic medication has also proven to be effective in adults. However, many children and adolescents can't access CBT, and some refuse or fail it~ antipsychotics have significant side effects. Alternative augmentation strategies are needed. Second, abnormalities in glutamatergic neurotransmission in orbitofrontal-striatal brain circuits are believed to underlie OCD, and preliminary studies suggest that medications that modulate glutamate (e.g., riluzole, memantine) reduce OCD severity when added to SRIs. Minocycline also modulates glutamate, but unlike riluzole and memantine, it is approved by the Food and Drug Administration (for acne and bacterial infections) in children ages 8 and above and is available in generic formulation. Thus, it is an attractive agent for investigating the role of glutamate modulators in pediatric OCD. Finally, our pilot data suggest that minocycline leads to significant decreases in OCD symptoms in adolescents who remain symptomatic despite an adequate SRI trial. Specifically, we will recruit 45 children and adolescents (ages 8-2) with OCD who have clinically significant symptoms despite an adequate SRI trial. We will randomize them to minocycline or pill placebo for 12 weeks while they continue on a stable SRI dose. Consonant with the R34 mechanism, our specific aims are: 1) to assess the feasibility of this strategy by assessing its safety, acceptability, and tolerability~ 2) to conduct a small randomized controlled trial to estimate the effects of minocycline versus placebo when added to SRIs~ and 3) to explore minocyline's potential mechanism of action. To accomplish the latter, we will use state-of-the art magnetic resonance spectroscopy (MRS) methods to examine whether adding minocyline leads to detectable changes in striatal glutamate levels and whether either baseline striatal glutamate levels or changes in striatal glutamate levels are associated with treatment response. The innovation of this R34 is that it investigates the effects of minocycline, a medication for OCD with a novel mechanism of action, while simultaneously exploring the potential effects of minocycline on the brain by using state-of-the art MRS methods. By developing new interventions (Objective 3) and promoting discovery in the brain (Objective 1), we advance the NIMH strategic plan. PUBLIC HEALTH RELEVANCE: Obsessive-compulsive disorder (OCD) is a common, chronic, and debilitating illness that usually begins in childhood or adolescence, but many children and adolescents with OCD only partially respond to currently available treatments. This study will examine the feasibility, clinical efficacy, and potential mechanism of a novel medication treatment strategy: the addition of minocycline to serotonin reuptake inhibitors. Minocycline is already approved by the Food and Drug Administration for those 8 and above for acne and bacterial infections. If effective, minocycline could greatly improve the outcome of children and adolescents with OCD because it is cost effective and widely available in generic formulation.